PROJECT ABSTRACT Variable penetrance is a phenomenon where the severity of the effect of a genetic variant differs among individuals who carry it. We propose to study a specific type of modified penetrance caused by genetic interaction or epistasis in humans, where a regulatory variant in cis modifies the penetrance of coding variants of the target gene. We call this phenomenon haplotype epistasis. We will study this phenomenon using genetic data of the general human population and of diseases with different genetic architectures. First, we will study signals of purifying selection against specific haplotype combinations as a proxy of phenotypically relevant epistatic effects. This will shed light on the modes and prevalence of haplotype epistasis, and the role of epistatic selection in shaping the spectrum of genetic variation in humans. Second, haplotype epistasis has been shown to affect genetic disease risk in some specific examples, but this mechanism is rarely considered in genetic studies that typically analyze genetic variants one-by-one. We aim to characterize haplotype epistasis as a potentially important phenomenon in rare variants contributing to autism risk, common variants predisposing to diverse traits mapped by genome-wide association studies, and germline modifiers of somatic cancer driver mutations. Furthermore, we will validate 5-10 examples of epistasis by genome editing of human cell lines, followed by cellular phenotyping. In summary, our study integrates many domains in human genetics that are usually studied in isolation. It is the first systematic characterization of haplotype epistasis and has potential to bring forward an important paradigm of epistatic functional effects of genetic variants.